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Supplementary Figure 2 from PML/RARα-Regulated miR-181a/b Cluster Targets the Tumor Suppressor RASSF1A in Acute Promyelocytic Leukemia

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posted on 2023-03-30, 23:06 authored by Daniela Bräuer-Hartmann, Jens-Uwe Hartmann, Alexander Arthur Wurm, Dennis Gerloff, Christiane Katzerke, Maria Vittoria Verga Falzacappa, Pier Giuseppe Pelicci, Carsten Müller-Tidow, Daniel G. Tenen, Dietger Niederwieser, Gerhard Behre

Western blot analysis of p53 protein in puromycin and gfp sorted miR-ZIP-expressing NB4 cells. GAPDH was used as internal control. Values below the blots represent the median {plus minus} SD from three independent experiments.

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ARTICLE ABSTRACT

In acute promyelocytic leukemia (APL), all-trans retinoic acid (ATRA) treatment induces granulocytic maturation and complete remission of leukemia. microRNAs are known to be critical players in the formation of the leukemic phenotype. In this study, we report downregulation of the miR-181a/b gene cluster in APL blasts and NB4 leukemia cells upon ATRA treatment as a key event in the drug response. We found that miR-181a/b expression was activated by the PML/RARα oncogene in cells and transgenic knock-in mice, an observation confirmed and extended by evidence of enhanced expression of miR-181a/b in APL patient specimens. RNA interference (RNAi)-mediated attenuation of miR-181a/b expression in NB4 cells was sufficient to reduce colony-forming capacity, proliferation, and survival. Mechanistic investigations revealed that miR-181a/b targets the ATRA-regulated tumor suppressor gene RASSF1A by direct binding to its 3′-untranslated region. Enforced expression of miR-181a/b or RNAi-mediated attenuation of RASSF1A inhibited ATRA-induced granulocytic differentiation via regulation of the cell-cycle regulator cyclin D1. Conversely, RASSF1A overexpression enhanced apoptosis. Finally, RASSF1A levels were reduced in PML/RARα knock-in mice and APL patient samples. Taken together, our results define miR-181a and miR-181b as oncomiRs in PML/RARα-associated APL, and they reveal RASSF1A as a pivotal element in the granulocytic differentiation program induced by ATRA in APL. Cancer Res; 75(16); 3411–24. ©2015 AACR.

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